SFRP1 as a therapeutic target in Alzheimer’s disease: a druggable molecule involved in amyloid, synaptic, and inflammatory pathology

INTRODUCTION: Alzheimer's disease (AD), a leading cause of dementia worldwide, still lacks broadly effective disease-modifying therapies. Recent anti-amyloid monoclonal antibodies highlight both the promise and limitations of amyloid-only strategies. Secreted Frizzled-Related Protein 1 (SFRP1), a Wnt antagonist and endogenous inhibitor of the α-secretase ADAM10, has emerged as a glial- and choroid plexus-derived pathogenic factor promoting amyloidogenic APP processing and accumulation, neuroinflammation, and synaptic dysfunction. AREAS COVERED: We review SFRP1 regulation of ADAM10-dependent non-amyloidogenic APP processing; its accumulation in amyloid plaques and cerebrospinal fluid of AD patients, independently corroborated by unbiased proteomic studies; its role as an astrocyte-to-microglia amplifier of neuroinflammation; its contribution to synaptic and cognitive decline in transgenic models; and its emerging link to APOEε4. We also discuss antibody- and small-molecule-based neutralization strategies, including pharmacodynamic and stage-dependent data defining its therapeutic window. EXPERT OPINION: SFRP1 is a mechanistically validated, multifunctional target intersecting amyloid, inflammatory, and synaptic pathways upstream of plaque formation. Clinical translation requires sustained brain exposure without compromising safety, biomarker-guided early intervention, and management of systemic consequences from Wnt and ADAM10 de-repression. Addressing these challenges could establish anti-SFRP1 therapy as a complementary, mechanistically distinct AD treatment.